Project Summary/Abstract. Aging is the single greatest risk factor for many different diseases, and most dramatically for neurodegenerative diseases, including Alzheimer's disease (AD). Overwhelming evidence links Alzheimer's disease to metabolic status and mitochondrial function, both cellular processes that are tightly controlled through complex signaling cascades. At the nexus is the mechanistic Target of Rapamycin (TOR), a central regulator of aging and age-related disease. If TOR signaling is perturbed, cellular processes can go awry, leading to altered metabolism, dysfunctional mitochondria and cell death. Indeed, hyperactive TOR is found across many models of Alzheimer's disease, and TOR inhibition has been shown to ameliorate cognitive decline in mouse models of Alzheimer's disease. More recently, the hypoxia-inducible factor (HIF), a transcription factor that controls the expression of hundreds of genes that regulate response to changing oxygen availability and glucose metabolism, has also been identified as a factor in aging, and, like TOR, as a protective factor against neurodegeneration, including AD. HIF and TOR have been shown to interact, but the details of if and how these signaling pathways overlap or regulate each other, and the extent to which they modify susceptibility to AD, represent a large gap in our understanding of mechanisms of aging and disease pathogenesis. While these and other well-known loci affect AD risk, all known genetic risk factors for AD account for a fraction of the naturally occurring variation in risk and severity of AD. Given the observation that mTOR and HIF appear to play important roles both in aging and AD, these findings suggest that close analysis of these pathways could help close this critical gap in our understanding of AD. The primary goal of this proposal is to define the mechanisms by which TOR signaling, HIF signaling, and natural variation that affects these pathways, modify susceptibility to A?- and tau- induced degeneration. In particular, I will use Drosophila models of AD, combined with natural genetic variation, to pursue three distinct, but complementary approaches to elucidate the relationship between TOR signaling, HIF signaling, and naturally occurring modifiers of A?42 and tau-induced degeneration. First, I will explore the molecular mechanisms that link altered TOR signaling and AD. Second, I will investigate the extent to which increased HIF signaling modifies A?42 and tau-induced degeneration in a Drosophila model of AD. Third, I will take advantage of the substantial natural variation in age-related risk of neurodegeneration that we have found to identify genes and downstream signaling pathways that modulate degeneration in a genetically variable population of Drosophila. These studies will significantly advance our understanding of disease mechanisms in Alzheimer's disease and mitochondrial disease, identify high- and low- risk populations, and elucidate the role of TOR and HIF in aging and Alzheimer's disease.